Polymorphic forms and co-crystals of a c-Met inhibitor

ABSTRACT

Provided herein are novel polymorphic forms and co-crystals of a compound useful in the treatment, prevention, or amelioration of cancer. In particular, the invention provides polymorphs and co-crystals of 6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one, which is an inhibitor of c-Met.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Divisional of U.S. patent application Ser. No.15/293,511, which was filed Oct. 14, 2016, which is a continuation ofPCT/US2015/026296, filed Apr. 17, 2015, which claims the benefit under35 U.S.C. § 119(e) of U.S. Provisional Patent Application Ser. No.61/981,158 filed Apr. 17, 2014, the disclosure of each of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION Field of the Invention

The present disclosure relates to novel polymorphic and co-crystal formsof6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one,methods for their preparation, and methods for their use.

Description of Related Technology

The hepatocyte growth factor receptor (“c-Met”) is a unique receptortyrosine kinase shown to be overexpressed in a variety of malignancies.The ligand for c-Met is hepatocyte growth factor (also known as scatterfactor, HGF and SF). Various biological activities have been describedfor HGF through interaction with c-Met (Hepatocyte Growth Factor-ScatterFactor (HGF-SF) and the c-Met Receptor, Goldberg and Rosen, eds.,Birkhauser Verlag-Basel, 67-79 (1993). HGF and c-Met are expressed atabnormally high levels in a large variety of solid tumors. High levelsof HGF and/or c-Met have been observed in liver, breast, pancreas, lung,kidney, bladder, ovary, brain, prostate, gallbladder and myeloma tumorsin addition to many others. Overexpression of the c-Met oncogene hasalso been suggested to play a role in the pathogenesis and progressionof thyroid tumors derived from follicular epithelium (Oncogene,7:2549-2553 (1992)). HGF is a morphogen (Development, 110:1271-1284(1990); Cell, 66:697-711 (1991)) and a potent angiogenic factor (J. CellBiol., 119:629-641 (1992)).

Some [1,2,4]triazolo[4,3-a]-pyridine compounds, such as6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one,are selective inhibitors of the c-Met receptor, and therefore, areuseful in the treatment, prevention, or amelioration of cancer. See,e.g., U.S. Pat. Nos. 8,212,041, 8,217,177, and 8,198,448, each of whichis incorporated herein by reference in its entirety.

SUMMARY

Disclosed herein are novel, free base polymorphic forms and novel,co-crystalline forms of6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one(“Compound M”), which is a selective inhibitor of the c-Met receptor,and useful in the treatment, prevention, or amelioration of cancer:

In one aspect, there is a free base monohydrate form of Compound M. Inembodiments, the free base monohydrate form of Compound M can becrystalline. The free base monohydrate form of Compound M can becharacterized by an X-ray powder diffraction pattern comprising peaks atabout 6.6, 7.9, 14.5, 15.1, 15.8 and 22.2±0.2° 2 θ using Cu Kαradiation. The free base monohydrate form of Compound M can be formedby, for example: (a) preparing a slurry comprising Compound M in anorganic solvent that is free or substantially free of each or all ofDMSO, propylene glycol, PEG 400, and acetone, wherein the slurrycomprises at least about 0.25 water activity, and isolating theresulting solid; or, (b) exposing an anhydrous form I of Compound M toat least about 25% relative humidity.

In another aspect, there is a free base acetone solvate form of CompoundM. In embodiments, the free base acetone solvate form of Compound M caninclude about a 1:1 molar ratio of acetone to Compound M. The free baseacetone solvate form of Compound M can be characterized by an X-raypowder diffraction pattern comprising peaks at about 7.2, 15.5, 17.1,22.0, and 23.1±0.2° 2 θ using Cu Kα radiation. In embodiments, the freebase acetone solvate form of Compound M can be formed by preparing aslurry of the free base monohydrate form of Compound M in acetone, andisolating the resulting solid.

In yet another aspect there is a free base dimethylsulfoxide (DMSO)hemisolvate form of Compound M. In embodiments, the free base DMSOhemisolvate form of Compound M can include about a 1:2 molar ratio ofDMSO to Compound M. The free base DMSO hemisolvate form of Compound Mcan be characterized by an X-ray powder diffraction pattern comprisingpeaks at about 7.3, 13.9, 14.3, 16.2, and 27.8±0.2° 2 θ using Cu Kαradiation. In embodiments, the free base DMSO hemisolvate form ofCompound M can be formed by preparing a slurry of the free basemonohydrate form of Compound M in DMSO, and isolating the resultingsolid.

In still another aspect, there is a free base anhydrous form of CompoundM. In embodiments, the free base anhydrous form of Compound M can becrystalline. The free base anhydrous form of Compound M can becharacterized by an X-ray powder diffraction pattern comprising peaks atabout 7.2, 8.2, 14.7, 16.4, and 23.1±0.2° 2 θ using Cu Kα radiation,and/or a hydration onset in a range of 24% to 31% relative humidity at atemperature in a range of 25° C. to 45° C. In these embodiments, thefree base anhydrous form is referred to herein as the free base“anhydrous I” form of Compound M. The free base anhydrous I form ofCompound M can be formed by, for example: (a) heating the free basemonohydrate form of Compound M to a temperature greater than 45° C.; or(b) subjecting the free base monohydrate form of Compound M to arelative humidity of less than about 15%; or (c) preparing a slurry ofthe free base monohydrate form of Compound M in an organic solvent thatis not DMSO or acetone, wherein the slurry comprises less than about0.15 water activity, and isolating the resulting solid.

The free base anhydrous form of Compound M can be characterized by anX-ray powder diffraction pattern comprising peaks at about 7.6, 8.9,11.5, 11.9, and 13.4±0.2° 2 θ using Cu Kα radiation. In theseembodiments, the free base anhydrous form is referred to herein as thefree base “anhydrous II” form of Compound M.” In embodiments, the freebase anhydrous II form of Compound M can be formed by desiccating asolid powder of the acetone solvate form of Compound M, and rehydratingthe desiccated solid at no less than about 30% relative humidity.

In another aspect, there is a free base amorphous form of Compound M.The free base anhydrous form of Compound M can be characterized by, forexample, an X-ray powder diffraction spectrum substantially as appearsin FIG. 6A and/or a differential scanning calorimetry thermographsubstantially as appears in FIG. 6B. In embodiments, the free baseamorphous form of Compound M can be formed by evaporating a crudereaction mixture of Compound M onto a substrate, purifying the crudereaction mixture via flash chromatography, collecting the resultingsolution, and evaporating the solvent.

In still another aspect, there is a co-crystal form of Compound M. Inembodiments, the co-crystal can include a coformer selected from thegroup consisting of phosphoric acid, maleic acid, succinic acid, sorbicacid, glutaric acid, and urea.

In embodiments wherein the coformer is phosphoric acid, the co-crystalform can include about a 1:1 molar ratio of phosphoric acid to CompoundM, and can be characterized by an X-ray powder diffraction patterncomprising peaks at about 9.4, 12.7, 17.3, 21.1, and 23.1±0.2° 2 θ usingCu Kα radiation.

In embodiments wherein the coformer is maleic acid, the co-crystal formcan include about a 1:1 molar ratio of maleic acid to Compound M, andcan be characterized by an X-ray powder diffraction pattern comprisingpeaks at about 10.0, 12.6, 17.5, 21.1, and 23.3±0.2° 2 θ using Cu Kαradiation.

In embodiments wherein the coformer is succinic acid, the co-crystalform can include about a 2:1 molar ratio of succinic acid to Compound M,and can be characterized by an X-ray powder diffraction patterncomprising peaks at about 5.3, 10.7, 12.5, 13.7, and 26.8±0.2° 2 θ usingCu Kα radiation.

In embodiments wherein the coformer is sorbic acid, the co-crystal formcan include about a 2:1 molar ratio of sorbic acid to Compound M, andcan be characterized by an X-ray powder diffraction pattern comprisingpeaks at about 7.9, 8.5, 9.7, 17.2, and 22.5±0.2° 2 θ using Cu Kαradiation.

In embodiments wherein the coformer is glutaric acid, the co-crystalform can include about a 2:1 molar ratio of glutaric acid to Compound M,and can be characterized by an X-ray powder diffraction patterncomprising peaks at about 6.7, 7.0, 10.7, 15.3, and 21.0±0.2° 2 θ usingCu Kα radiation.

In embodiments wherein the coformer is urea, the co-crystal form caninclude about a 1:1 molar ratio of urea to Compound M, and can becharacterized by an X-ray powder diffraction pattern comprising peaks atabout 8.1, 8.9, 16.1, 21.0, and 28.4±0.2° 2 θ using Cu Kα radiation.

Another aspect of the disclosure is use or administration of any one ofthe compounds described herein for selective inhibition of the c-Metreceptor, and optionally for use in the treatment, prevention, oramelioration of cancer.

For the compositions and methods described herein, optional features,including but not limited to components, compositional ranges thereof,substituents, conditions, and steps, are contemplated to be selectedfrom the various aspects, embodiments, and examples provided herein.

Further aspects and advantages will be apparent to those of ordinaryskill in the art from a review of the following detailed description,taken in conjunction with the drawings. While the polymorphic forms andco-crystalline forms of Compound M are susceptible of embodiments invarious forms, the description hereafter includes specific embodimentswith the understanding that the disclosure is illustrative, and is notintended to limit the invention to the specific embodiments describedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts an X-ray powder diffraction (XRPD) pattern of the freebase monohydrate form of Compound M.

FIG. 1B depicts a single crystal X-ray diffraction (XRD) structure ofthe free base monohydrate form of Compound M.

FIG. 1C depicts a differential scanning calorimetry (DSC) thermograph(top trace) and a thermogravimetric analysis (TGA) trace (bottom trace)of the free base monohydrate form of Compound M when the sample isheated from 25° C. at a rate of 10° C./min.

FIG. 1D depicts a DSC thermograph of the free base monohydrate form ofCompound M when the sample is heated from 5° C. at a rate of 10° C./min(top trace) and 2° C./min (bottom trace).

FIG. 1E depicts an isotherm plot of the free base monohydrate form ofCompound M obtained from a dynamic vapor sorption experiment.

FIG. 1F depicts a near-IR spectrum of the free base monohydrate form ofCompound M (solid line) and the anhydrous I form of Compound M (dashedline).

FIG. 2A depicts an XRPD pattern of the free base anhydrous I form ofCompound M.

FIG. 2B depicts a single crystal XRD structure of the free baseanhydrous I form of Compound M.

FIG. 2C depicts a TGA trace (top trace), a standard DSC thermograph(middle trace), and a hermetic DSC thermograph (bottom trace) of theanhydrous I form of Compound M when the sample is heated from 25° C. ata rate of 10° C./min.

FIG. 3A depicts an XRPD pattern of a mixture of the free base anhydrousI and anhydrous II forms of Compound M.

FIG. 3B depicts a DSC thermograph of the free base anhydrous II form ofCompound M when the sample is heated from 25° C. at a rate of 2° C./min(top trace) and 10° C./min (bottom trace).

FIG. 4A depicts an XRPD pattern of the free base acetone solvate form ofCompound M.

FIG. 4B depicts a DSC thermograph of the free base acetone solvate formof Compound M when the sample is heated from 25° C. at a rate of 10°C./min.

FIG. 5A depicts an XRPD pattern of the free DMSO hemisolvate form ofCompound M.

FIG. 5B depicts a single crystal XRD structure of the free base DMSOhemisolvate form of Compound M.

FIG. 5C depicts a DSC thermograph of the free base DMSO hemisolvate formof Compound M.

FIG. 6A depicts an XRPD pattern of the free base amorphous form ofCompound M.

FIG. 6B depicts a DSC thermograph of the free base amorphous form ofCompound M.

FIG. 7A depicts an XRPD pattern of a phosphoric acid co-crystal ofCompound M.

FIG. 7B depicts a DSC thermograph (top trace) and a TGA trace (bottomtrace) of the phosphoric acid co-crystal of Compound M when the sampleis heated from 25° C. at a rate of 10° C./min.

FIG. 8A depicts an XRPD pattern of a maleic acid co-crystal of CompoundM.

FIG. 8B depicts a DSC thermograph (bottom trace) and a TGA trace (toptrace) of the maleic acid co-crystal of Compound M when the sample isheated from 25° C. at a rate of 10° C./min.

FIG. 9A depicts an XRPD pattern of a succinic acid co-crystal ofCompound M.

FIG. 9B depicts a DSC thermograph (bottom trace) and a TGA trace (toptrace) of the succinic acid co-crystal of Compound M when the sample isheated from 25° C. at a rate of 10° C./min.

FIG. 10A depicts an XRPD pattern of a sorbic acid co-crystal of CompoundM.

FIG. 10B depicts a DSC thermograph (bottom trace) and a TGA trace (toptrace) of the sorbic acid co-crystal of Compound M when the sample isheated from 25° C. at a rate of 10° C./min.

FIG. 11A depicts an XRPD pattern of a glutaric acid co-crystal ofCompound M.

FIG. 11B depicts a DSC thermograph (bottom trace) and a TGA trace (toptrace) of the glutaric acid co-crystal of Compound M when the sample isheated from 25° C. at a rate of 10° C./min.

FIG. 12A depicts an XRPD pattern of a urea co-crystal of Compound M.

FIG. 12B depicts a single crystal XRD structure of a urea co-crystal ofCompound M.

FIG. 12C depicts a DSC thermograph (top trace) and a TGA trace (bottomtrace) of the urea co-crystal of Compound M when the sample is heatedfrom 25° C. at a rate of 10° C./min.

FIG. 13 depicts a pH-solubility profile of the free base monohydrateform of Compound M.

DETAILED DESCRIPTION

Provided herein are novel, free base polymorphic forms and novel,co-crystalline forms of6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one(“Compound M”):

Each polymorph and co-crystal described herein can be made from CompoundM. Methods and processes relating to the preparation of Compound M aredisclosed in co-pending U.S. Provisional Patent application Ser. No.61/838,856, which is incorporated herein by reference in its entirety.

The polymorphic forms and co-crystalline forms of Compound M, theirmethods of preparation, and their methods of use are contemplated toinclude embodiments including any combination of one or more of theadditional optional elements, features, and steps further describedbelow (including those shown in the figures), unless stated otherwise.

In jurisdictions that forbid the patenting of methods that are practicedon the human body, the meaning of “administering” of a composition to ahuman subject shall be restricted to prescribing a controlled substancethat a human subject will self-administer by any technique (e.g.,orally, inhalation, topical application, injection, insertion, etc.).The broadest reasonable interpretation that is consistent with laws orregulations defining patentable subject matter is intended. Injurisdictions that do not forbid the patenting of methods that arepracticed on the human body, the “administering” of compositionsincludes both methods practiced on the human body and also the foregoingactivities.

As used herein, the term “comprising” indicates the potential inclusionof other agents, elements, steps, or features, in addition to thosespecified.

As used herein, the term “polymorphs” or “polymorphic forms” refers tocrystal forms of the same molecule. Different polymorphic forms of amolecule have different physical properties as a result of thearrangement or conformation of the molecules in the crystal lattice.Some of the different physical properties include melting temperature,heat of fusion, solubility, dissolution rate, and/or or vibrationalspectra. The physical form of a particular compound is particularlyimportant when the compound is used in a pharmaceutical formulationbecause different solid forms of a compound result in differentproperties of the drug product.

Polymorphs of a molecule can be obtained by a number of methods, asshown in the art, such as, for example, melt recrystallization, meltcooling, solvent recrystallization, desolvation, rapid evaporation,rapid cooling, slow cooling, vapor diffusion, and sublimation.Techniques for characterizing a polymorph include X-ray powderdiffraction (XRPD), single crystal X-ray diffraction (XRD), differentialscanning calorimetry (DSC), vibrational spectroscopy (e.g., IR and Ramanspectroscopy), solid state nuclear magnetic resonance (ssNMR), hot stageoptical microscopy, scanning electron microscopy (SEM), electroncrystallography and quantitative analysis, particle size analysis (PSA),surface area analysis, solubility studies, and dissolution studies.

As used herein, the term “solvate” refers to a crystal form of asubstance that contains an association between a substrate and asolvent.

As used herein, the term “hemisolvate” refers to a solvate containingone molecule of solvent per two molecules of the substrate.

As used herein, the term “hydrate” refers to a solvate wherein thesolvent is water.

As used herein, the term “monohydrate” refers a hydrate that containsone molecule of water per one molecule of the substrate.

As used herein, the term “crystalline” refers to a solid in which theconstituent atoms, molecules, or ions are arranged in a regularlyordered, repeating pattern in three dimensions.

As used herein, the term “co-crystal” refers to a crystalline materialthat comprises two or more unique components held together by weakinteractions (e.g., hydrogen bonding, pi-stacking, guest-hostcomplexation, and/or van der Waals forces), wherein each component is asolid under ambient conditions when in its pure form. Each co-crystalcontains distinctive physical characteristics, such as structure,melting point, and heat of fusion. The term “co-crystal” does notinclude salts, which are distinguished by proton transfer to result inan electrostatic linkage between oppositely charged ions, or solvates,which are associations of substrates with solvents (i.e., liquids atambient temperature) from which they are crystallized, as defined above.

As used herein, the term “amorphous” refers to a solid that lacks thelong-range order of a crystal.

If there is a discrepancy between a depicted chemical structure and achemical name given to that structure, the depicted chemical structurecontrols.

Free Base Monohydrate Form of Compound M

In one aspect, the disclosure provides a free base monohydrate form ofCompound M. In various embodiments of this aspect, the free basemonohydrate form of Compound M is crystalline. Embodiments of the freebase monohydrate form of Compound M can be characterized by one or moreof the parameters described in further detail below.

The free base monohydrate form of Compound M has an aqueous solubilityof about 0.26 mg/mL at a pH in a range of about 4 to about 7 and atemperature of about 20° C. to about 25° C. The solubility of the freebase monohydrate form of Compound M increases slightly at acidic pH,increases significantly in the presence of surfactants, and decreasesslightly at higher ionic strength. For example, the free basemonohydrate form of Compound A has a solubility of 0.35 mg/mL at pH 2,1.44 mg/mL in 0.25% (w/v) SDS, and 0.18 mg/mL in PBS, as described inExample 1. The free base monohydrate form of Compound M is soluble inorganic solvents, such as, for example, methanol, ethanol, isopropanol,acetonitrile, ethyl acetate, methyl ethyl ketone, and DMSO/watermixtures, as described in Example 3.

The free base monohydrate from of Compound M is non-hygroscopic. Forexample, when subjected to dynamic vapor sorption, as described in theMethods section, the free base monohydrate form of Compound Mdemonstrated a total weight gain of about 0.2 wt. % between about 40%and about 90% relative humidity, as depicted in FIG. 1E.

The free base monohydrate form of Compound M is stable under acceleratedstability testing conditions, when subjected to chemical stress, andwhen subjected for photostress. For example, the free base monohydrateform of Compound M remains in substantially the same physical form over12 weeks at 25° C. and 60% relative humidity or at 40° C. and 75%relative humidity. Further still, the free base monohydrate form ofCompound M exhibits low levels of degradation under photostressconditions (lx ICH dose for UV and vis light exposure), such as 0.2%under visible conditions and 0.4% under UV conditions, as described inExample 4. In embodiments, the free base monohydrate form of Compound Mcan be characterized by an X-ray powder diffraction pattern, obtained asset forth in the Methods section, having peaks at about 6.6, 7.9, 14.5,15.1, 15.8 and 22.2±0.2° 2θ using Cu Kα radiation. The free basemonohydrate form of Compound M optionally can be further characterizedby an X-ray powder diffraction pattern having additional peaks at about12.4, 13.2, 17.8, 18.1, 19.4, 19.7, 20.5, 23.6, 25.7±0.2° 2θ using Cu Kαradiation. In embodiments, the free base monohydrate form of Compound Mcan be characterized by an X-ray powder diffraction patternsubstantially as depicted in FIG. 1A.

In one embodiment, the free base monohydrate form of Compound M can becharacterized by a single crystal X-ray diffraction (XRD) structure,obtained as set forth in the Methods section, wherein the free basemonohydrate form comprises a monoclinic space group of P2₁ and unit cellparameters of about a=12.2708(6) Å, b=6.8666(4) Å, c=14.6871(9) Å, andβ=113.580(4)°. The free base monohydrate form of Compound M optionallycan be further characterized by the XRD parameters in the table, below,and as represented in FIG. 1B.

Wavelength 1.54178 Å Crystal system Monoclinic Space group P2₁ Unit celldimensions a = 12.2708(6) Å α = γ = 90° b = 6.8666(4) Å β = 113.580(4)°c = 14.6871(9) Å Volume 1134.19(11) Å³ Z 2 Density (calculated) 1.410Mg/m³ Flack parameter 0.1(3)

The free base monohydrate form of Compound M can be characterized by itsdehydration onset obtained by, for example, differential scanningcalorimetry (DSC), hot stage microscopy, and dynamic vapor sorption(DVS) methods.

DSC thermographs were obtained as set forth in the Methods section. Thedehydration of the free base monohydrate form of Compound M is a kineticevent that is influenced by experimental parameters. Thus, inembodiments, the free base monohydrate form of Compound M can becharacterized by a DSC thermograph having a dehydration endotherm withan onset in a range of about 40° C. to about 55° C. when the free basemonohydrate form is heated in an open aluminum pan. For example, inembodiments wherein the free base monohydrate of Compound M is heatedfrom about 25° C. at a rate of about 10° C./min, the free basemonohydrate of Compound M can be characterized by a DSC thermographhaving a dehydration endotherm with an onset of about 55° C. and a peakat about 84° C., as shown in FIG. 1C (top trace). In embodiments whereinthe free base monohydrate of Compound M is heated from 5° C. at a rateof about 10° C./min, the free base monohydrate of Compound M can becharacterized by a DSC thermograph having a dehydration endotherm withan onset of about 44° C. and a peak at about 74° C., as shown in FIG. 1D(top trace). In embodiments wherein the free base monohydrate ofCompound M is heated from 5° C. at a rate of about 2° C./min, the freebase monohydrate of Compound M can be characterized by a DSC thermographhaving a dehydration endotherm with an onset of about 26° C. and a peakat about 46° C., as shown in FIG. 1D (bottom trace). In embodiments, thefree base monohydrate form of Compound M can be characterized by a DSCthermograph substantially as depicted in FIG. 1C (top trace) and/or 1D.

In embodiments, the free base monohydrate form of Compound M can becharacterized by a dehydration onset, obtained via DVS experiments asset forth in the Methods section, in a range of about 15% to about 25%relative humidity at a temperature in a range of about 25° C. to about45° C.

The free base monohydrate form of Compound M can be characterized bythermogravimetric analysis (TGA). The dehydration of the free basemonohydrate form of Compound M is a kinetic event that is influenced byexperimental parameters. TGA thermographs were obtained as set forth inthe Methods section. Thus, in embodiments, the free base monohydrateform of Compound M can be characterized by a weight loss in a range ofabout 3.0% to about 3.8%, with an onset temperature in a range of about20° C. to about 25° C. For example, the free base monohydrate from ofCompound M can be characterized by a weight loss of about 3.6%, with anonset at about 25° C., as depicted in FIG. 1C (bottom trace). Inembodiments, the free base monohydrate form of Compound M can becharacterized by a TGA trace substantially as depicted in FIG. 1C(bottom trace).

The free base monohydrate form of Compound M can be characterized bynear-IR, as set forth in the Methods section. In embodiments, the freebase monohydrate form of Compound M can be characterized by a near-IRspectrum having a water band at 1850-2000 nm. For example, the free basemonohydrate form of Compound M can be characterized by a near-IRspectrum substantially as depicted in FIG. 1F (solid line).

The free base monohydrate form of Compound M can be formed in a varietyof ways. In one type of embodiment, the free base monohydrate form ofCompound M can be formed by preparing a slurry containing Compound M inan organic solvent that is free or substantially free of each or all ofDMSO, propylene glycol, PEG 400, and acetone, wherein the slurrycomprises at least about 0.25 water activity, and then isolating theresulting solid. For example, the free base monohydrate form of CompoundM can be formed by preparing a slurry containing Compound M inacetonitrile/water, and then isolating the resulting substrate. Inanother type of embodiment, the free base monohydrate form of Compound Mcan be formed by exposing a free base anhydrous form I of Compound M toat least about 25% relative humidity.

Free Base Anhydrous Form of Compound M

In another aspect, the disclosure provides a free base anhydrous form ofCompound M.

In various embodiments, the free base anhydrous form of Compound M canbe crystalline. The free base anhydrous form of Compound M can becharacterized by one or more of the parameters described below.

The free base anhydrous form of Compound M can be characterized by anX-ray powder diffraction pattern, obtained as set forth in the Methodssection, having peaks at about 7.2, 8.2, 14.7, 16.4, and 23.1±0.2° 2θusing Cu Kα radiation. When the free base anhydrous form of Compound Mis characterized by the aforementioned XRPD peaks, then the form isreferred to herein as the free base “anhydrous I” form of Compound M.The free base anhydrous I form of Compound M optionally can be furthercharacterized by an X-ray powder diffraction pattern having additionalpeaks at about 13.0, 17.9, 19.4, 20.4, 23.9, 24.8, 26.1, 28.1, 28.9,29.8±0.2° 2θ using Cu Kα radiation. In embodiments, the free baseanhydrous I form of Compound M can be characterized by an X-ray powderdiffraction pattern substantially as depicted in FIG. 2A.

In one embodiment, the free base anhydrous I form of Compound M can becharacterized by a single crystal XRD structure, obtained as set forthin the Methods section, wherein the free base anhydrous form comprises amonoclinic space group of P2₁ and unit cell parameters of abouta=12.2395(2) Å, b=7.10130(10) Å, c=13.7225(2) Å, and β=116.1010(10)°.The free base anhydrous I form of Compound M optionally can be furthercharacterized by the XRD parameters in the table, below, and asrepresented in FIG. 2B.

Crystal system Monoclinic Space group P2₁ Unit cell dimensions a =12.2395(2) Å; α = 90° b = 7.10130(10) Å; β = 116.1010(10)° c =13.7225(2) Å; γ = 90° Volume 1071.08(3) Å³ Z 2 Density (calculated)1.437 mg/m³

The free base anhydrous I form of Compound M can be characterized by DSCthermographs, obtained as set forth in the Methods section. Inembodiments, the free base anhydrous I form of Compound M can becharacterized by a DSC thermograph having a melt endotherm with an onsetin a range of about 151° C. to about 153° C. when the anhydrous I formis heated in an open aluminum pan. For example, when embodiments of thefree base anhydrous I form of Compound M are heated from about 25° C. ata rate of about 10° C./min, the free base anhydrous I form of Compound Mcan be characterized by a DSC thermograph having a melt endotherm withan onset of about 152° C., as depicted in FIG. 2C (middle trace). Inembodiments, the free base anhydrous I form of Compound M can becharacterized by a DSC thermograph substantially as depicted in FIG. 2C(middle trace).

In embodiments, the free base anhydrous I form of Compound M can becharacterized by TGA. TGA thermographs were obtained as set forth in theMethods section. Thus, in embodiments, the free base anhydrous I form ofCompound M can be characterized by substantially no weight loss, asdepicted in FIG. 2C (top trace).

In embodiments, the free base anhydrous I form of Compound M can becharacterized by a hydration onset, obtained using moisture sorptionexperiments as described in the Methods section, in a range of 24% to31% relative humidity at a temperature in a range of 25° C. to 45° C.

The free base anhydrous I form of Compound M can be characterized bynear-IR, as set forth in the Methods section. Thus, in some embodiments,the free base anhydrous I form of Compound M can be characterized by anear-IR spectrum having no water band at 1850-2000 nm. For example, thefree base anhydrous I form of Compound M can be characterized by anear-IR spectrum substantially as depicted in FIG. 1F (dashed line).

The free base anhydrous I form of Compound M can be formed in a varietyof ways. In one type of embodiment, the free base anhydrous I form ofCompound M is prepared by heating the free base monohydrate form ofCompound M to a temperature greater than 45° C. For example, the freebase anhydrous I form of Compound I can be prepared by heating the freebase monohydrate form of Compound M to at least about 45° C. at arelative humidity below 30%.

In another type of embodiment, the free base anhydrous I form ofCompound M is prepared by subjecting the free base monohydrate form ofCompound M to a relative humidity of less than about 15%. For example,the free base anhydrous I form of Compound M can be prepared bysubjecting the free base monohydrate form of Compound M to a relativehumidity of less than about 15% at a temperature in a range of about 25°C. to about 45° C.

In yet another type of embodiment, the free base anhydrous I form ofCompound M is formed by preparing a slurry of the free base monohydrateform of Compound M in an organic solvent that is not DMSO or acetone,wherein the slurry comprises less than 0.15 water activity, andisolating the resulting solid.

The free base anhydrous form of Compound M can be characterized by anX-ray powder diffraction pattern, obtained as set forth in the Methodssection, having peaks at about 7.6, 8.9, 11.5, 11.9, and 13.4±0.2° 2θusing Cu Kα radiation. When the free base anhydrous form of Compound Mis characterized by the aforementioned XRPD peaks, then the form isreferred to herein as the free base “anhydrous II” form of Compound M.The free base anhydrous II form of Compound M optionally can be furthercharacterized by an X-ray powder diffraction pattern having additionalpeaks at about 15.5, 16.5, 23.0, and 24.9±0.2° 2θ using Cu Kα radiation.A XRPD pattern depicting a mixture of the free base anhydrous I andanhydrous II forms of Compound M is shown in FIG. 3A.

The free base anhydrous II form of Compound M can be characterized byDSC, as set forth in the Methods section. In embodiments, the free baseanhydrous II form of Compound M can be characterized by a DSCthermograph having an endothermic event at a temperature in a range ofabout 100° C. to about 120° C. when the anhydrous II form of Compound Mis heated in an open aluminum pan. For example, when embodiments of thefree base anhydrous form II of Compound M are heated from about 25° C.at a rate of about 10° C./min, the free base anhydrous II form ofCompound M can be characterized by a DSC thermography having anendothermic event with an onset of about 110° C. and a peak at about115° C., as shown in FIG. 3B (bottom trace). In embodiments, the freebase anhydrous II form of Compound M can be characterized by a DSCthermograph substantially as depicted in FIG. 3B (bottom trace).

The free base anhydrous II form of Compound M can be formed in a varietyof ways. In one type of embodiment, the free base anhydrous II form ofCompound M can be prepared by desiccating a solid powder of the acetonesolvate form of Compound M, and rehydrating the desiccated solid at noless than about 30% relative humidity.

Acetone Solvate Form of Compound M

In another aspect, the disclosure provides an acetone solvate form ofCompound M. The acetone solvate form of Compound M can be characterizedby one or more of the parameters described below.

In embodiments, the acetone solvate form of Compound M can include abouta 1:1 molar ratio of acetone to Compound M.

The free base acetone solvate form of Compound M can be characterized byan X-ray powder diffraction pattern, obtained as set forth in theMethods section, having peaks at about 7.2, 15.5, 17.1, 22.0, and23.1±0.2° 2θ using Cu Kα radiation. The free base acetone solvate formof Compound M optionally can be further characterized by an X-ray powderdiffraction pattern having additional peaks at about 20.6 and 24.8±0.2°2θ using Cu Kα radiation. In embodiments, the free base acetone solvateform of Compound M can be characterized by an X-ray powder diffractionpattern substantially as depicted in FIG. 4A.

The free base acetone solvate form of Compound M can be characterized byits DSC thermograph, obtained as set forth in the Methods section. Inembodiments, the free base acetone solvate form of Compound M can becharacterized by a DSC thermograph, obtained at a heating rate of 10°C./min, having and endothermic event with an onset at about 114° C. witha peak at about 117° C., as depicted in FIG. 4B. In embodiments, thefree base acetone solvate form of Compound M can be characterized by aDSC thermograph substantially as depicted in FIG. 4B.

The free base acetone solvate form of Compound M can be formed in avariety of ways. In one type of embodiment, the free base acetonesolvate form of Compound M can be formed by preparing a slurry of thefree base monohydrate form of Compound M in acetone, and isolating theresulting solid.

DMSO Hemisolvate Form of Compound M

In another aspect, the disclosure provides a dimethylsulfoxide (DMSO)hemisolvate form of Compound M. The DMSO hemisolvate form of Compound Mhas a solubility of about 164 mg/mL at a temperature in the range ofabout 20 to about 25° C. The DMSO hemisolvate form of Compound M can becharacterized by one or more of the parameters described below.

In embodiments, the DMSO hemisolvate form of Compound M can includeabout a 1:2 molar ratio of DMSO to Compound M.

The free base DMSO hemisolvate form of Compound M can be characterizedby an X-ray powder diffraction pattern, obtained as set forth in theMethods section, having peaks at about 7.3, 13.9, 14.3, 16.2, and27.8±0.2° 2θ using Cu Kα radiation. The free base DMSO hemisolvate formof Compound M optionally can be further characterized by an X-ray powderdiffraction pattern having additional peaks at about 12.1, 15.0, 15.4,15.6, 18.6, 20.6, 21.2, 22.0, 22.6, and 23.2±0.2° 2θ using Cu Kαradiation. In some embodiments, the free base DMSO hemisolvate form ofCompound M can be characterized by an X-ray powder diffraction patternsubstantially as depicted in FIG. 5A.

In one embodiment, the free base DMSO hemisolvate form of Compound M canbe characterized by a single crystal XRD pattern, obtained as set forthin the Methods section, wherein the free base DMSO hemisolvate formcomprises a monoclinic space group of C2 and unit cell parameters ofabout a=25.6737(16) Å, b=8.2040(5) Å, c=24.1194(12) Å, andβ=107.436(4)°. The free base DMSO hemisolvate form of Compound Moptionally can be further characterized by the XRD parameters in thetable, below, and as represented in FIG. 5B.

Wavelength 1.54178 Å Crystal system Monoclinic Space group C2 Unit celldimensions a = 25.6737(16) Å α = γ = 90° b = 8.2040(5) Å β = 107.436(4)°c = 24.1194(12) Å Volume 4846.8(5) Å³ Z 8 Density (calculated) 1.377Mg/m³ Flack parameter 0.02(6)

The free base DMSO hemisolvate form of Compound M can be characterizedby a DSC thermograph, as set forth in the Methods section. Inembodiments, the free base DMSO hemisolvate form of Compound M can becharacterized by a DSC thermograph, obtained at a heating rate of 10°C./min, and having a first melting event at about 114° C., and/or arecrystallization exotherm at about 117° C., and/or a melt onsettemperature at about 150° C., as depicted in FIG. 5C. In embodiments,the free base DMSO hemisolvate form of Compound M can be characterizedby a DSC thermograph substantially as depicted in FIG. 5C.

The free base DMSO hemisolvate form of Compound M can be formed in avariety of ways. In one type of embodiment, the free base DMSOhemisolvate form of Compound M can be formed by preparing a slurry ofthe free base monohydrate form of Compound M in DMSO, and isolating theresulting solid.

Amorphorus Form of Compound M

In still another aspect, the disclosure provides an amorphous form ofCompound M. The amorphous form of Compound M can be characterized by oneor more of the parameters described below.

In embodiments, the free base amorphous form of Compound M can becharacterized by an XRPD pattern, obtained as set forth in the Methodssection, having no defined peaks. For example, the free base amorphousform of Compound M can be characterized by an XRPD pattern substantiallyas depicted in FIG. 6A.

In embodiments, the free base amorphous form of Compound M can becharacterized by a DSC trace, obtained as set forth in the Methodssection, showing a glass transition (Tg) at about 72° C. For example,the free base amorphous form of Compound M can be characterized by a DSCthermograph substantially as depicted in FIG. 6B.

The free base amorphous form of Compound M can be formed in a variety ofways. In one type of embodiment, the free base amorphous form ofCompound M can be formed by evaporating a crude reaction mixture ofCompound M onto a substrate (e.g., silica gel), purifying the crudereaction mixture via flash chromatography, collecting the resultingsolution, and evaporating the solvent.

Co-Crystal Forms of Compound M

In another aspect, the disclosure provides a co-crystal form of CompoundM having a co-crystal forming compound (“coformer”) selected from thegroup consisting of phosphoric acid, maleic acid, succinic acid, sorbicacid, glutaric acid, and urea.

Phosphoric Acid Co-Crystal of Compound M

In one type of embodiment, the coformer is phosphoric acid. In theseembodiments, the phosphoric acid co-crystal of Compound M can includeabout a 1:1 molar ratio of phosphoric acid to Compound M. The phosphoricacid co-crystal form of Compound M can be characterized by an XRPDpattern, obtained as set forth in the Methods section, having peaks atabout 9.4, 12.7, 17.3, 21.1, and 23.1±0.2° 2θ using Cu Kα radiation. Thephosphoric acid co-crystal form of Compound M optionally can be furthercharacterized by an X-ray powder diffraction pattern having additionalpeaks at about 6.7, 7.8, 13.2, 15.7, 19.5, 20.5, and 24.8±0.2° 2θ usingCu Kα radiation. In embodiments, the phosphoric acid co-crystal form ofCompound M can be characterized by an X-ray powder diffraction patternsubstantially as depicted in FIG. 7A.

The phosphoric acid co-crystal of Compound M can be characterized by aDSC thermograph, as set forth in the Methods section. In embodiments,the phosphoric acid co-crystal of Compound M can be characterized by aDSC thermograph having a melt endotherm with an onset in a range ofabout 166° C. to about 169° C. when the phosphoric acid co-crystal isheated in an open aluminum pan. For example, when embodiments of thephosphoric acid co-crystal of Compound M are heated from about 25° C. ata rate of about 10° C./min, the phosphoric acid co-crystal of Compound Mcan be characterized by a DSC thermograph having a melt endotherm withan onset of about 168° C., as depicted in FIG. 7B (top trace). Inembodiments, the phosphoric acid co-crystal of Compound M can becharacterized by a DSC thermograph substantially as depicted in FIG. 7B(top trace).

In embodiments, the phosphoric acid co-crystal of Compound M can becharacterized by TGA, as set forth in the Methods section. Thus, inembodiments, the phosphoric acid co-crystal of Compound M can becharacterized by a TGA trace substantially as depicted in FIG. 7B(bottom trace).

Maleic Acid Co-Crystal of Compound M

In another type of embodiment, the coformer is maleic acid. In theseembodiments, the maleic acid co-crystal of Compound M can include abouta 1:1 molar ratio of maleic acid to Compound M. The maleic acidco-crystal form of Compound M can be characterized by an XRPD pattern,obtained as set forth in the Methods section, having peaks at about10.0, 12.6, 17.5, 21.1, and 23.3±0.2° 2θ using Cu Kα radiation. Themaleic acid co-crystal form of Compound M optionally can be furthercharacterized by an X-ray powder diffraction pattern having additionalpeaks at about 7.7, 8.3, 15.7, 19.5, 20.5, and 22.3±0.2° 2θ using Cu Kαradiation. In embodiments, the maleic acid co-crystal form of Compound Mcan be characterized by an X-ray powder diffraction patternsubstantially as depicted in FIG. 8A.

The maleic acid co-crystal of Compound M can be characterized by a DSCthermograph, as set forth in the Methods section. In embodiments, themaleic acid co-crystal of Compound M can be characterized by a DSCthermograph having a melt endotherm with an onset in a range of about151° C. to about 154° C. when the maleic acid co-crystal of Compound Mis heated in an open aluminum pan. For example, when embodiments of themaleic acid co-crystal of Compound M are heated from about 25° C. at arate of about 10° C./min, the maleic acid co-crystal of Compound M canbe characterized by a DSC thermograph having a melt endotherm with anonset of about 152° C., as depicted in FIG. 8B (bottom trace). Inembodiments, the maleic acid co-crystal of Compound M can becharacterized by a DSC thermograph substantially as depicted in FIG. 8B(bottom trace).

In embodiments, the maleic acid co-crystal of Compound M can becharacterized by TGA. TGA thermographs were obtained as set forth in theMethods section. Thus, in embodiments, the maleic acid co-crystal ofCompound M can be characterized by a TGA trace substantially as depictedin FIG. 8B (top trace).

In embodiments, the maleic acid co-crystal of Compound M can becharacterized by ¹H NMR, as set forth in the Methods section. Forexample, the maleic acid co-crystal of Compound M can be characterizedby an NMR spectrum having the following peaks: ¹H NMR (400 MHz,DMSO-d₆): δ 8.69 (d, J=3.0 Hz, 1H), 8.48 (d, J=1.1 Hz, 1H), 8.18 (s,1H), 8.02 (d, J=3.0 Hz, 1H), 7.84 (d, J=0.8 Hz, 1H), 7.67 (dd, J=12.1Hz, J=1.2 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 6.94 (q, J=7.1 Hz, 1H), 6.76(d, J=7.7 Hz, 1H), 6.24 (s, 2H), 4.30 (m, 2H), 3.89 (s, 3H), 3.71 (m,2H), 2.43 (s, 8H), 1.99 (d, J=7.1 Hz, 3H).

Succinic Acid Co-Crystal of Compound M

In yet another type of embodiment, the coformer is succinic acid. Inthese embodiments, the succinic acid co-crystal of Compound M caninclude about a 2:1 molar ratio of succinic acid to Compound M. Thesuccinic acid co-crystal form of Compound M can be characterized by anXRPD pattern, obtained as set forth in the Methods section, having peaksat about 5.3, 10.7, 12.5, 13.7, and 26.8±0.2° 2θ using Cu Kα radiation.The succinic acid co-crystal form of Compound M optionally can befurther characterized by an X-ray powder diffraction pattern havingadditional peaks at about 7.4, 17.9, 19.7, 20.8, 21.6, 23.2, 25.8, 27.9,and 28.6±0.2° 2θ using Cu Kα radiation. In embodiments, the succinicacid co-crystal form of Compound M can be characterized by an X-raypowder diffraction pattern substantially as depicted in FIG. 9A.

The succinic acid co-crystal of Compound M can be characterized by a DSCthermograph, as set forth in the Methods section. In embodiments, thesuccinic acid co-crystal of Compound M can be characterized by a DSCthermograph having a melt endotherm with an onset in a range of about148° C. to about 154° C. when the succinic acid co-crystal is heated inan open aluminum pan. For example, when embodiments of the succinic acidco-crystal of Compound M are heated from about 25° C. at a rate of about10° C./min, the succinic acid co-crystal of Compound M can becharacterized by a DSC thermograph having a melt endotherm with an onsetof about 151° C., as depicted in FIG. 9B (bottom trace). In embodiments,the succinic acid co-crystal of Compound M can be characterized by a DSCthermograph substantially as depicted in FIG. 9B (bottom trace).

In embodiments, the succinic acid co-crystal of Compound M can becharacterized by TGA. TGA thermographs were obtained as set forth in theMethods section. Thus, in embodiments, the succinic acid co-crystal ofCompound M can be characterized by a TGA trace substantially as depictedin FIG. 9B (top trace).

In embodiments, the succinic acid co-crystal of Compound M can becharacterized by ¹H NMR, as set forth in the Methods section. Forexample, the succinic acid co-crystal of Compound M can be characterizedby an NMR spectrum having the following peaks: ¹H NMR (400 MHz,DMSO-d₆): δ 12.12 (bs, ˜3-4H), 8.70 (d, J=3.0 Hz, 1H), 8.49 (d, J=1.2Hz, 1H), 8.18 (s, 1H), 8.03 (d, J=2.6 Hz, 1H), 7.85 (d, J=0.8 Hz, 1H),7.68 (dd, J=12.1 Hz, J=1.2 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 6.95 (q,J=7.2 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 4.31 (m, 2H), 3.89 (s, 3H), 3.72(m, 2H), 2.43 (s, 8H), 2.00 (d, J=7.1 Hz, 3H).

Sorbic Acid Co-Crystal of Compound M

In still another type of embodiment, the coformer is sorbic acid. Inthese embodiments, the sorbic acid co-crystal of Compound M can includeabout a 2:1 molar ratio of sorbic acid to Compound M. The sorbic acidco-crystal form of Compound M can be characterized by an XRPD pattern,obtained as set forth in the Methods section, having peaks at about 7.9,8.5, 9.7, 17.2, and 22.4±0.2° 2θ using Cu Kα radiation. The sorbic acidco-crystal form of Compound M optionally can be further characterized byan X-ray powder diffraction pattern having additional peaks at about11.5, 13.1, 15.3, 18.3, 20.3, 21.7, 23.6, 25.0, and 27.9±0.2° 2θ usingCu Kα radiation. In embodiments, the sorbic acid co-crystal form ofCompound M can be characterized by an X-ray powder diffraction patternsubstantially as depicted in FIG. 10A.

The sorbic acid co-crystal of Compound M can be characterized by a DSCthermograph, as set forth in the Methods section. In embodiments, thesorbic acid co-crystal of Compound M can be characterized by a DSCthermograph having an endotherm with an onset in a range of about 102°C. to about 106° C. when the sorbic acid co-crystal is heated in an openaluminum pan. For example, in embodiments wherein the sorbic acidco-crystal of Compound M is heated from about 25° C. at a rate of about10° C./min, the sorbic acid co-crystal of Compound M can becharacterized by a DSC thermograph having an endotherm with an onset ofabout 104° C., as shown in FIG. 10B (bottom trace). In embodiments, thesorbic acid co-crystal of Compound M can be characterized by a DSCthermograph substantially as depicted in FIG. 10B (bottom trace).

In embodiments, the sorbic acid co-crystal of Compound M can becharacterized by TGA. TGA thermographs were obtained as set forth in theMethods section. Thus, in embodiments, the sorbic acid co-crystal ofCompound M can be characterized by a TGA trace substantially as depictedin FIG. 10B (top trace).

In embodiments, the sorbic acid co-crystal of Compound M can becharacterized by ¹H NMR, as set forth in the Methods section. Forexample, the sorbic acid co-crystal of Compound M can be characterizedby an NMR spectrum having the following peaks: ¹H NMR (400 MHz,DMSO-d₆): δ 12.09 (bs, 2H), 8.69 (d, J=3.0 Hz, 1H), 8.48 (d, J=1.1 Hz,1H), 8.17 (s, 1H), 8.02 (d, J=3.0 Hz, 1H), 7.84 (d, J=0.9 Hz, 1H), 7.67(dd, J=12.1 Hz, J=1.2 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.14 (dd, J=15.1Hz, J=10.1 Hz, 2H), 6.94 (q, J=7.0, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.24(m, 4H), 5.77 (m, 2H) 4.30 (m, 2H), 3.89 (s, 3H), 3.71 (m, 2H), 1.99 (d,J=7.0 Hz, 3H), 1.81 (m, 6H).

Glutaric Acid Co-Crystal of Compound M

In another type of embodiment, the coformer is glutaric acid. In theseembodiments, the glutaric acid co-crystal of Compound M can includeabout a 2:1 molar ratio of glutaric acid to Compound M. The glutaricacid co-crystal form of Compound M can be characterized by an XRPDpattern, obtained as set forth in the Methods section, having peaks atabout 6.7, 7.0, 10.7, 15.3, and 21.0±0.2° 2θ using Cu Kα radiation. Theglutaric acid co-crystal form of Compound M optionally can be furthercharacterized by an X-ray powder diffraction pattern having additionalpeaks at about 7.9, 13.5, 14.7, 16.2, 18.3, 19.1, 20.6, 23.2, 24.7, and25.3±0.2° 2θ using Cu Kα radiation. In embodiments, the glutaric acidco-crystal form of Compound M can be characterized by an X-ray powderdiffraction pattern substantially as depicted in FIG. 11A.

The glutaric acid co-crystal of Compound M can be characterized by a DSCthermograph, as set forth in the Methods section. In embodiments, theglutaric acid co-crystal of Compound M can be characterized by a DSCthermograph having an endotherm with an onset in a range of about 75° C.to about 82° C. and/or in a range of about 113° C. to about 115° C. whenthe glutaric acid co-crystal is heated in an open aluminum pan. Forexample, in embodiments wherein the glutaric acid co-crystal of CompoundM is heated from about 25° C. at a rate of about 10° C./min, theglutaric acid co-crystal of Compound M can be characterized by a DSCthermograph having endotherms with onsets of about 82° C. and about 114°C., as shown in FIG. 11B (bottom trace). In embodiments, the sorbic acidco-crystal of Compound M can be characterized by a DSC thermographsubstantially as depicted in FIG. 11B (bottom trace).

In embodiments, the glutaric acid co-crystal of Compound M can becharacterized by TGA. TGA thermographs were obtained as set forth in theMethods section. Thus, in embodiments, the glutaric acid co-crystal ofCompound M can be characterized by a TGA trace substantially as depictedin FIG. 11B (top trace).

In embodiments, the glutaric acid co-crystal of Compound M can becharacterized by ¹H NMR, as set forth in the Methods section. Forexample, the glutaric acid co-crystal of Compound M can be characterizedby an NMR spectrum having the following peaks: ¹H NMR (400 MHz,DMSO-d₆): δ 12.06 (bs, 4H), 8.70 (d, J=3.0 Hz, 1H), 8.49 (d, J=1.1 Hz,1H), 8.18 (s, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.68(dd, J=12.1 Hz, J=1.2 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 6.95 (q, J=7.0Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 4.31 (m, 2H), 3.90 (s, 3H), 3.72 (m,2H), 2.25 (t, J=7.4 Hz, ˜8-9H), 2.00 (d, J=7.0 Hz, 3H), 1.71 (quin,J=7.3 Hz, 4H).

Urea Co-Crystal of Compound M

In yet another type of embodiment, the coformer is urea, wherein theurea co-crystal of Compound M can include about a 1:1 molar ratio ofurea to Compound M. The urea co-crystal form of Compound M can becharacterized by an XRPD pattern, obtained as set forth in the Methodssection, having peaks at about 8.1, 8.9, 16.1, 21.0, and 28.4±0.2° 2θusing Cu Kα radiation. The urea co-crystal form of Compound M optionallycan be further characterized by an X-ray powder diffraction patternhaving additional peaks at about 11.2, 14.2, 16.6, 17.5, 17.9, 19.9,22.4, 24.5, and 25.8±0.2° 2θ using Cu Kα radiation. In embodiments, theurea co-crystal form of Compound M can be characterized by an X-raypowder diffraction pattern substantially as depicted in FIG. 12A.

In one embodiment, the urea co-crystal form of Compound M can becharacterized by a single crystal XRD structure, obtained as set forthin the Methods section, wherein the urea co-crystal form of Compound Mcomprises a monoclinic space group of P2₁ and unit cell parameters ofabout a=4.7057(2) Å, b=22.7810(11) Å, c=10.9512(6) Å, and β=91.361(2)°.The urea co-crystal form of Compound M optionally can be furthercharacterized by the XRD parameters in the table below, and asrepresented in FIG. 12B.

Crystal system Monoclinic Space group P2₁ Wavelength 0.71073 Å Unit celldimensions a = 4.7057(2) Å; α = 90°. b = 22.7810(11) Å; β = 91.361(2)° c= 10.9512(6) Å; γ = 90° Volume 1173.64(10) Å³ Z 2 Density (calculated)1.481 mg/m³

The urea co-crystal of Compound M can be characterized by a DSCthermograph, as set forth in the Methods section. In embodiments, theurea co-crystal of Compound M can be characterized by a DSC thermographhaving endotherms with onsets in a range of about 177° C. to about 179°C. when the urea co-crystal is heated in an open aluminum pan. Forexample, in embodiments wherein the urea co-crystal of Compound M isheated from about 25° C. at a rate of about 10° C./min, the ureaco-crystal of Compound M can be characterized by a DSC thermographhaving an endotherm with an onset of about 178° C., as shown in FIG. 12C(top trace). In embodiments, the urea co-crystal of Compound M can becharacterized by a DSC thermograph substantially as depicted in FIG. 12C(top trace).

In embodiments, the urea co-crystal of Compound M can be characterizedby TGA. TGA thermographs were obtained as set forth in the Methodssection. Thus, in embodiments, the urea co-crystal of Compound M can becharacterized by a TGA trace substantially as depicted in FIG. 12C(bottom trace).

In embodiments, the urea co-crystal of Compound M can be characterizedby ¹H NMR, as set forth in the Methods section. For example, the ureaco-crystal of Compound M can be characterized by an NMR spectrum havingthe following peaks: ¹H NMR (400 MHz, DMSO-d₆): δ 8.70 (d, J=3.0 Hz,1H), 8.49 (d, J=1.1 Hz, 1H), 8.19 (s, 1H), 8.03 (d, J=3.0 Hz, 1H), 7.85(d, J=0.8 Hz, 1H), 7.69 (dd, J=12.1 Hz, J=1.2 Hz, 1H), 7.62 (d, J=7.8Hz, 1H), 6.95 (q, J=7.2 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 5.39 (bs, 4H),4.31 (tt, J=2.7 Hz, J=1.7 Hz, 2H), 3.90 (s, 3H), 3.72 (tt, J=2.5 Hz,J=1.8 Hz, 2H), 3.32 (s, 12H (6H urea co-crystal, 6H H₂O), 2.00 (d, J=7.0Hz, 3H).

It is contemplated that the polymorphs and co-crystals disclosed hereincan be used in the treatment, prevention, or amelioration of cancer, asdescribed in, e.g., U.S. Pat. Nos. 8,212,041, 8,217,177, and 8,198,448,and U.S. Provisional Patent Application Ser. No. 61/838,856.

Methods

X-ray powder diffraction data were obtained on a PANalytical X'Pert PROX-ray diffraction system with a Real Time Multiple Strip (RTMS)detector. Samples were scanned in continuous mode from 5-45° (2θ) with astep size of 0.0334° at 45 kV and 40 mA with CuKα radiation (1.54 Å).The incident beam path was equipped with a 0.02 rad soller slit, 15 mmmask, 4° fixed anti-scatter slit and a programmable divergence slit. Thediffracted beam was equipped with a 0.02 radian soller slit,programmable anti-scatter slit and a 0.02 mm nickel filter. Samples wereprepared on a low background sample holder and placed on a spinningstage with a rotation time of 2 s. For variable-temperature studies,samples were prepared on a flat plate sample holder and placed in aTTK-450 temperature control stage. For variable-humidity studies, RH-200generator (VTI) was used to control atmosphere in THC humidity samplechamber.

Differential scanning calorimetry (DSC) was performed on a TAInstruments Q100 calorimeter at in an aluminum Tzero pan under drynitrogen, flowing at 50 mL/min. Thermogravimetric analysis (TGA) wasperformed on a TA Instruments Q500 analyzer in a platinum pan under drynitrogen, flowing at 90 mL/min.

Moisture sorption data was collected using a Surface Measurement SystemsDVS-Advantage instrument. Equilibrium criteria were set at ±0.002%weight change in 5 minutes with a maximum equilibrium time of 360minutes.

Single crystal structures were determined as follows. Crystals weremounted on a Nylon loop using a very small amount of paratone oil. Datawere collected using a Bruker CCD (charge coupled device) baseddiffractometer equipped with an Oxford Cryostream low-temperatureapparatus operating at 173 K. Data were measured using omega and phiscans of 0.5° per frame for either 30 or 45 s. The total number ofimages was based on results from the program COSMO where redundancy wasexpected to be 4.0 and completeness to 100% out to 0.83 Å. Cellparameters were retrieved using APEX II software and refined using SAINTon all observed reflections. Data reduction was performed using theSAINT software which corrects for Lp. Scaling and absorption correctionswere applied using SADABS multi-scan technique. The structures weresolved by the direct method using the SHELXS-97 program and refined byleast squares method on F2, SHELXL-97, which are incorporated inSHELXTL-PC V 6.10.

Throughout the disclosure herein, crystal parameters, such as unit celldimensions, atomic coordinates, and the like, are provided in standardcrystallographic notation, such that the standard uncertainty for aspecific value is stated in parentheses. For example, a=12.2708(6) Åindicates a 95% chance that the value of ‘a’ is 12.2708±0.0006 (i.e.,lies between 12.2702 and 12.714 Å).

High performance liquid chromatography (HPLC) analyses were performed onan Agilent 1100 or 1200 series HPLC equipped with a binary pump,diode-array detector, thermostated column compartment, and auto sampler.Separation and elution was achieved using a reverse-phase column and0.1% triflouroacetic acid/water/acetonitrile mobile phase.

Liquid chromatography mass spectrometry was conducted on an Agilent 1100LC-MSD Trap SL equipped with an electrospray ionization source.Separation and elution was achieved using a reverse-phase column and0.1% formic acid/water/acetonitrile mobile phase. Mass spectra data werecollected in positive ion mode. Fragmentation data was generated usingAuto MS2 mode.

Near-IR spectroscopic analysis was performed using a FOSS NIRSystemsnear-IR spectrometer that consisted of XDS monochromator and either XDSRapid Liquid Analyzer or XDS Rapid Content Analyzer, depending on thesample being analyzed. Solid or slurry samples were analyzed directly insample vials, using empty vials as blanks.

¹H NMR was performed on a Bruker BioSpin 400 MHz instrument. Solidsamples were dissolved in DMSO-d₆ and transferred to NMR tubes foranalysis.

EXAMPLES

The following examples are provided for illustration and are notintended to limit the scope of the invention

Example 1: Aqueous Solubility of the Free Base Monohydrate Form ofCompound M

The equilibrium solubility of the free base monohydrate form of CompoundM in water was measured in several experiments a temperature in therange of about 20 to 25° C., as shown in the table, below. The aqueoussolubility was found to be 0.26 mg/mL and no changes in crystal formwere observed based on XRPD analysis of the isolated solid.

Solubility of the Monohydrate Form in Aqueous Media

Duration (h) Isolation Method pH Solubility (mg/mL) Sample 1 40 1 4.700.253 Sample 2 138 1 4.09 0.259 Sample 3 69 2 6.85 0.262 1 - Centrifuge0.05 mL of sample at 15000 rpm for 30 minutes. Analyze supernatant. 2 -Centrifuge 0.5 mL of sample at 15000 rpm for 30 minutes. Analyzesupernatant

The solubility of the free base monohydrate form of Compound M also wasdetermined in several aqueous media, as shown in the table, below. Inall studies, excess solid of the compound was allowed to equilibrate ata temperature in the range of about 20 to 25° C. for 12-48 hours whilestirring.

Media pH Solubility (mg/mL) PBS 6.9 0.18 0.01N HCl 1.9 0.35 FaSIF² 6.80.44 SGF³ 2.1 1.44 ²FaSIF is composed of 5 mM Na Taurocholate 1.5 mMLecithin in 0.029M KH₂PO₄ 0.22M KCl pH 6.8 ³SGF is 0.25% (w/v) SDS 0.2%(w/v) NaCl in 0.01N HCl

The solubility of the monohydrate form decreased slightly in presence ofhigher ionic strength (PBS), and increased to 0.35 mg/mL in the acidichydrochloric acid solution. The solubility of the monohydrate form alsoincreased significantly in the presence of surfactants (FaSIF and SGF).The aqueous solubility of the monohydrate form increased significantlywhen subjected to a pH less than one. For example, at pH 0.73 (adjustedwith HCl), the solubility of the monohydrate form was 9.74 mg/mL and atpH 0.80, (adjusted with methane sulfonic acid), the solubility of themonohydrate form was 12.37 mg/mL.

Example 2: pH-Solubility Profile of the Free Base Monohydrate Form ofCompound M

The pH-solubility profile (see FIG. 13) of the free base monohydrateform of Compound M was obtained in a universal buffer system containing0.5M phosphoric acid, acetic acid, boric acid, sodium hydroxide andsodium chloride in a pH range between 1.17 and 8.95. The experimentalsetup and analysis was performed using Symyx platform.

Example 3: Solubility of Select Free Base Forms of Compound M in OrganicSolvents

The solubility of the free base monohydrate form of Compound M in selectorganic solvents at a temperature in the range of about 20 to 25° C. wasdetermined, as shown in the table, below. In all studies, excess solidof the compound was allowed to equilibrate for at least 12 hours whilestirring.

Solubility of Monohydrate Form in Various Organic Solvents

Solubility, Solvent mg/mL Polymorphic Form Methanol 53.9 monohydrateEthanol 29.7 monohydrate Isopropanol 8.80 monohydrate Acetonitrile 127monohydrate (extra peak observed) Ethyl Acetate 20.1 monohydrate MethylEthyl Ketone 45.8 monohydrate + trace acetone solvate 25% Dimethylsulfoxide in water 0.59 monohydrate 50% Dimethyl sulfoxide in water 1.02monohydrate 75% Dimethyl sulfoxide in water 8.45 monohydrate Toluene1.90 monohydrate

Example 4: Photostability Studies of the Free Base Monohydrate andAmorphous Forms of Compound M

When a solid powder sample of the free base monohydrate form of CompoundA was exposed to photolytic conditions (1×ICH dose for UV and visiblelight), no chemical degradation of samples in amber glass vials wasobserved. As shown in the table below minimal degradation, 0.4% and0.2%, was detected in samples in clear glass vials under UV and visiblelight, respectively.

Degradation of Solid Monohydrate Compound M after Exposure to UV-VisLight

Area % (215 nm) UV (200 W × h/m²) Visible (1200 klux × h) Peak RRT AmberClear Amber Clear No MS signal 0.80 <0.01 0.02 <0.01 <0.01 m/z 581 0.82<0.01 0.05 <0.01 <0.01 m/z 520 [M + Na]⁺ 0.83 <0.01 0.06 <0.01 <0.01 m/z390 0.84 0.06 0.19 0.05 0.13 monohydrate 1.00 99.89 99.64 99.89 99.83m/z 638 1.16 0.05 0.04 0.05 0.04 Total Impurities 0.11 0.36 0.11 0.17 %Recovery 101.4% 99.7% 100.9% 99.6%

Example 5: Solid State Stability of the Free Base Monohydrate Form ofCompound M

Solid samples of the free base monohydrate form of Compound M wereplaced under accelerated stability testing conditions (25° C./60% RH,40° C./75% RH and 60° C./ambient RH) for 12 weeks. As shown in thetable, below, no changes in solid state properties were observed.

Solid State Stability of the Monohydrate Form of Compound M—AcceleratedConditions

Week 2 Week 4 Week 8 Week 12 Initial 25/60 40/75 60° C. 25/60 40/75 60°C. 25/60 40/75 60° C. 25/60 40/75 −20° C. Peak RRT Area % (215 nm)monohydrate 1.00 100.0 99.18 99.35 99.21 99.90 99.86 99.90 99.97 99.9299.97 100.0 100.0 100.0 2 1.09 <0.1 0.27 0.31 0.25 <0.1 <0.1 <0.1 <0.1<0.1 <0.1 <0.1 <0.1 <0.1 3 1.25 <0.1 0.28 0.35 0.27 <0.1 <0.1 <0.1 <0.1<0.1 <0.1 <0.1 <0.1 <0.1 4 1.53 <0.1 0.28 <0.1 0.27 <0.1 <0.1 <0.1 <0.1<0.1 <0.1 <0.1 <0.1 <0.1 Total Impurities <0.1 0.82 0.65 0.79 0.01 0.14<0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 % API Recovery 100.2 100.3 100.8100.4 100.8 100.6 101.0 101.1 101.1 100.9 100.0 100.2 99.5 DSC,Dehydration Onset, ° C. 45.4 48.0 48.9 44.2 46.1 45.0 47.7 55.3 48.847.1 46.7 48.6 45.1 ΔH, J/g 96 118 121 80 111 110 109 103 101 104 104109 90 DSC, Melt Onset, ° C. 152.5 152.5 152.8 152.5 152.5 152.9 152.5152.4 152.4 152.0 152.4 152.5 151.7 ΔH, J/g 71 70 69 73 69 70 71 70 6970 70 77 74 TGA, % Wt Loss 3.63 3.51 3.61 3.43 3.48 4.32 3.30 3.55 3.433.45 3.34 3.42 3.21

Example 6: Preparation of the Free Base Monohydrate Form of Compound M

The free base monohydrate form of Compound M can be formed in a varietyof ways. For example, the free base monohydrate form of Compound M wasformed by exposing a free base anhydrous I form of Compound M to arelative humidity above 15%. The free base monohydrate form of CompoundM also was prepared by subjecting a free base anhydrous form of CompoundM to 30% relative humidity, to result in a fully hydrated compound at40% relative humidity, with a weight gain of 3.7 wt. %. As anotherexample, the free base monohydrate form of Compound M was formed bypreparing a slurry containing Compound M in acetonitrile/water throughthe anti-solvent addition of water, and then isolating the resultingcompound.

Single crystals of the free base monohydrate form of Compound M weregrown from acetone solution.

Example 7: Preparation of the Free Base Anhydrous I Form of Compound M

The free base anhydrous I form of Compound M can be formed in a varietyof ways. For example, the free base anhydrous I form of Compound M wasprepared by heating the free base monohydrate form of Compound M to 55°C. The free base anhydrous I form of Compound M also was prepared bysubjecting the free base monohydrate form of Compound M to a relativehumidity of less than 15%, at 25° C., The free base anhydrous I form ofCompound M also was prepared by slurrying the free base monohydrate formof Compound M in propylene glycol at a concentration of about 14 mg/mLfor at least 8 hours at a temperature in a range of 20° C. to 25° C.,and isolating the solids by filtration. In another experiment, the freebase anhydrous I form of Compound M was prepared by slurrying the freebase monohydrate form of Compound M in PEG 400 at a concentration ofabout 14 mg/mL for at least 8 hours at a temperature in a range of 20°C. to 25° C., and isolating the solids by filtration

Single crystals of the free base anhydrous I form of Compound M weregrown by preparing a solution of Compound M in ethanol, and placing thesolution in a desiccator with phosphorous pentoxide (20% relativehumidity).

Example 8: Preparation of the Free Base Anhydrous II Form of Compound M

The free base anhydrous II form of Compound M can be formed in a varietyof ways. For example, the free base anhydrous II form of Compound M wasformed by desiccating a solid powder of the form of the acetone solvateform of Compound M, and rehydrating the desiccated solid at greater than30% relative humidity. In another example, the free base anhydrous IIform of Compound M was prepared by incubating the acetone solvate formof Compound M at a temperature in a range of 20° C. to 25° C. in adesiccator for up to eight months, and then storing the resultingproduct at a temperature in a range of 20° C. to 25° C. and humidity inthe range of about 20 to about 30% for 19 hours.

Example 9: Preparation of the Free Base Acetone Solvate Form of CompoundM

The free base acetone solvate form of Compound M can be formed in avariety of ways. For example, the free base acetone solvate form ofCompound M was prepared by slurrying the free base monohydrate form ofCompound M with about 3.5 volumes of acetone for about 4 hours at atemperature in a range of 20° C. to 25° C., and then isolating theresulting solids by filtration.

Example 10: Preparation of the Free Base DMSO Hemisolvate Form ofCompound M

The free base DMSO hemisolvate form of Compound M can be formed in avariety of ways. For example, the free base DMSO hemisolvate form ofCompound M was prepared by slurrying the free base monohydrate form ofCompound M in 2.5 volumes of DMSO at a temperature in a range of 20° C.to 25° C. for 70 hours, and isolating the solids by filtration.

Single crystals of the free base DMSO hemisolvate form of Compound Mwere prepared by slow evaporation of a saturated DMSO solution.

Example 11: Preparation of the Free Base Amorphous Form of Compound M

The free base amorphous form of Compound M can be formed in a variety ofways. For example, the free base amorphous form of Compound M was formedby evaporating a crude reaction mixture of Compound M onto silica gelplaced in tandem with the column (330 g REDISEP, well equilibrated) andpurified via flash chromatography (10 minutes at 100% CH₂Cl₂, then 50minutes of gradient from 0% to 5% of 1% ammonium hydroxide in methanol).The desired compound solution was collected and evaporated using rotaryevaporator, yielding solids of the free base amorphous form of CompoundM.

Example 12: Preparation of Co-Crystal Forms of Compound M

The co-crystal forms of Compound M were prepared by, for example,solution crystallization, cooling and evaporation, precipitation, or viaa slurry of Compound M and the coformer in a solvent, such asethanol/acetone, ethanol/ethyl acetate, acetone/acetic acid, isopropylalcohol (IPA), acetonitrile, ethyl acetate, or ethanol.

The phosphoric acid co-crystal of Compound M was prepared by solutionrecrystallization using a 1:1 molar ratio of Compound M and phosphoricacid in ethanol/acetone The phosphoric acid co-crystal of Compound Malso was prepared by solution crystallization using a 1:1 molar ratio ofCompound M and phosphoric acid in acetone/acetic acid.

The maleic acid co-crystal of Compound M was prepared by slurrycrystallization using a 1:1 molar ratio of Compound M and anhydrousmaleic acid in IPA.

The succinic acid co-crystal of Compound M was prepared by cooling andevaporation using a 2:1 molar ratio of Compound M and anhydrous succinicacid in IPA, or a 2:1 molar ratio of Compound M and anhydrous succinicacid in acetonitrile, or a 2:1 molar ratio of Compound M and anhydroussuccinic acid in ethanol.

The sorbic acid co-crystal of Compound M was prepared by evaporationusing a 2:1 molar ratio of Compound M and anhydrous sorbic acid inethanol.

The glutaric acid co-crystal of Compound M was prepared by cooling andevaporation using a 2:1 molar ratio of Compound M and anhydrous glutaricacid in ethanol.

The urea co-crystal of Compound M was prepared by adding Compound M to asolution of urea in ethanol using 4:1 molar ratio of Compound M andanhydrous urea, followed by slow crystallization of the co-crystal form.

The foregoing description is given for clearness of understanding only,and no unnecessary limitations should be understood therefrom, asmodifications within the scope of the invention may be apparent to thosehaving ordinary skill in the art.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise” and variations such as“comprises” and “comprising” will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

Throughout the specification, where compositions are described asincluding components or materials, it is contemplated that thecompositions can also consist essentially of, or consist of, anycombination of the recited components or materials, unless describedotherwise. Likewise, where methods are described as including particularsteps, it is contemplated that the methods can also consist essentiallyof, or consist of, any combination of the recited steps, unlessdescribed otherwise. The invention illustratively disclosed hereinsuitably may be practiced in the absence of any element or step which isnot specifically disclosed herein.

The practice of a method disclosed herein, and individual steps thereof,can be performed manually and/or with the aid of or automation providedby electronic equipment. Although processes have been described withreference to particular embodiments, a person of ordinary skill in theart will readily appreciate that other ways of performing the actsassociated with the methods may be used. For example, the order ofvarious of the steps may be changed without departing from the scope orspirit of the method, unless described otherwise. In addition, some ofthe individual steps can be combined, omitted, or further subdividedinto additional steps.

All patents, publications and references cited herein are hereby fullyincorporated by reference. In case of conflict between the presentdisclosure and incorporated patents, publications and references, thepresent disclosure should control.

We claim:
 1. A free base form of6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one,wherein the free base form is selected from the group consisting of anacetone solvate form and a dimethylsulfoxide (DMSO) hemisolvate form. 2.The free base form of claim 1, wherein the free base form is the acetonesolvate form.
 3. The free base form of claim 2, wherein the acetonesolvate form comprises about a 1:1 molar ratio of acetone to6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one.4. The free base form of claim 2, wherein the acetone solvate form ischaracterized by an X-ray powder diffraction pattern comprising peaks atabout 7.2, 15.5, 17.1, 22.0, and 23.1±0.2° 20 using Cu Kα radiation. 5.A method of preparing an acetone solvate form of6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one,the method comprising preparing a slurry of a monohydrate form of6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-onein acetone, and isolating the resulting solid.
 6. The free base form ofclaim 1, wherein the free base form is the DMSO hemisolvate form.
 7. Thefree base form of claim 6, wherein the DMSO hemisolvate form comprisesabout a 1:2 molar ratio of DMSO to6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one.8. The free base form of claim 6, wherein the DMSO hemisolvate form ischaracterized by an X-ray powder diffraction pattern comprising peaks atabout 7.3, 13.9, 14.3, 16.2, and 27.8±0.2° 2θ using Cu Kα radiation. 9.A method of preparing a DMSO hemisolvate form of6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one,the method comprising preparing a slurry of the monohydrate form of6-{(1R)-1-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-onein DMSO, and isolating the resulting solid.